The development of an atomic model of tau filaments in Alzheimer?s disease (AD) has opened several new opportunities, including the ability to identify high-affinity ligands or antibodies to detect AD tau filaments (i.e., PET ligands, small molecule compounds, immunotherapy, biomarkers) and providing a clear directive about essential features that need to be recapitulated from a modeling perspective. Given that tauopathies are complex, pathogenic entities with significant heterogeneity in clinical presentation, disease course, and underlying pathology, it is essential that the tools under development are capable of detecting/recognizing the actual pathologies observed. As such, the overall goals of the current project are to characterize the heterogeneity of tau filaments across tauopathies, and to utilize structural features that define tau and TDP-43 filament morphology in sporadic and familial forms of disease to provide novel insight into pathogenesis and toxicity. In particular, we will assess and compare tau filament heterogeneity between AD and chronic traumatic encephalopathy (CTE) and develop novel resources to both detect and model tau in these distinct tauopathies. Similar methodology utilizing cryo-electron microscopy (cryo-EM) will also be employed to resolve filament structure in frontotemporal lobar degeneration (FTLD), which is the second most common cause of dementia after AD. As FTLD is usually characterized pathologically by the aberrant deposition of either tau (FTLD-tau) or TDP-43 (FTLD-TDP), we will develop atomic models of both tau and TDP-43 filaments in sporadic and familial forms of FTLD. Overlaying structural insights with our recent discovery of novel post-translational modifications (PTMs) of tau and TDP-43, we will assess the contribution of specific modifications to aggregation propensity, utilizing a combination of cryo-EM, mass spectrometry, molecular biology and biochemical approaches. These results will guide the continued development of resources to best detect and model particular aspects of pathology.